A process for the preparation of a key intermediate of meloxicam benzene sulfonic acid

Abstract

The application discloses a preparation method of a key intermediate of meloxicam. The application provides a preparation method of a compound IV, which comprises the following steps: step (1), a reaction of a compound III in a solvent under reflux conditions in the presence of a base; and step (2), a reaction of a product obtained in the step (1) in a solvent to obtain the compound IV. The preparation method is simple, low in cost, high in yield and high in purity, and has a good application prospect in industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a key intermediate of mirogabalin besylate. BACKGROUND

[0002] Peripheral neuropathic pain is caused by injury or dysfunction of peripheral nerves due to various causes, and typically includes diabetic and post-herpetic neuralgia. Peripheral neuropathic pain caused by diabetes is the most common long-term complication of diabetes patients, and the symptoms include sharp pain or hyperalgesia, numbness, loss of balance and coordination, tingling, burning, which are aggravated at night. The incidence of shingles is caused by the decline of immunity to varicella-zoster virus, which forms latent infection in the ganglion. In neuralgia, even after the cure of shingles, the burning pain or the pain like electricity penetrating the body still exists, and the disease is considered as a kind of intractable pain, which can cause muscle weakness and, in rare cases, paralysis.

[0003] Mirogabalin besylate, as a GABA (gamma-aminobutyric acid) analogue, can act on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely present in the nervous system mediating pain transmission and processing throughout the body), thereby playing a role in treating chronic neuropathic pain. It is a new type of drug for treating peripheral neuropathic pain developed by Japan's First Chemical, and its molecular formula is as follows:

[0004]

[0005] The reported synthesis methods of mirogabalin besylate all contain the key intermediate compound 3-ethylbicyclo[3.2.0]hept-3-en-6-one (compound I), and its structure is as follows:

[0006]

[0007] WO20010110361 reports a process for preparing compound I by using ethyl acetoacetate and 3-bromopropene as raw materials through four steps of reaction. However, ethyl acetoacetate has two α-carbon atoms, and the reaction site is not specific, which leads to a low yield of the process, and is not suitable for industrialization.

[0008]

[0009] WO2012169475 uses n-butyl aldehyde and allyl alcohol as raw materials, and generates heptadienoic acid through acetal reaction, Claisen rearrangement and Claisen-Schmidt condensation, and then generates the key intermediate compound I through intramolecular reaction. This route uses allyl alcohol as a liquid toxicant, and has a higher requirement for personal protection in production, which is not conducive to large-scale commercial production.

[0010]

[0011] WO2012169474 reported that n-butyl aldehyde and diisobutylamine were used as raw materials to condense to generate an enamine intermediate, then substituted with 3-bromoallyl to generate a quaternary ammonium salt, then subjected to a Wittig condensation to generate an intermediate heptadienoic acid, and then subjected to an intramolecular reaction to generate compound I. This route avoids the use of highly toxic allyl alcohol, and diisobutylamine is relatively expensive.

[0012]

[0013] CN117945887A used (E)-2-hexenoic acid ester as a raw material and 3-bromoallyl as a raw material to prepare heptadienoic acid by one-pot method. According to the above reported method, heptadienoic acid can be prepared by one step reaction to generate compound I, but (E)-2-hexenoic acid ester is very expensive and is not suitable for commercial production.

[0014] . SUMMARY

[0015] The present application provides a preparation method of a key intermediate of meloxicam phenylsulfonate. The preparation method is simple, low in cost, high in yield and high in purity, and has a good application prospect in industrial production.

[0016] The present application provides a preparation method of compound IV, which comprises the following steps:

[0017] Step (1): Compound III is subjected to a reaction in a solvent in the presence of a base under reflux conditions;

[0018] Step (2): The product obtained in step (1) is subjected to a reaction in a solvent to prepare compound IV;

[0019] ;

[0020] wherein, R 1 and R 2 are independently C1-C6 alkyl; or R 1 and R 2 are connected to form .

[0021] In a certain scheme of the present application, R 1 and R 2 are the same.

[0022] In an embodiment of the present application, the C1-C6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl or s-butyl; preferably methyl, ethyl or t-butyl.

[0023] In an embodiment of the present application, the compound III is , , or ; preferably , or .

[0024] In an embodiment of the present application, in step (1), the solvent is an organic solvent; preferably an alcohol solvent; for example, ethanol.

[0025] In an embodiment of the present application, in step (1), the base is an inorganic base; preferably an alkali metal hydroxide; for example, potassium hydroxide and / or sodium hydroxide.

[0026] In an embodiment of the present application, in step (1), the molar volume ratio of the compound III to the solvent is 1 mmol: (0.8-1.2) mL; preferably 1 mmol: 1 mL.

[0027] In an embodiment of the present application, in step (1), the molar ratio of the compound III to the base is 1: (1-2); preferably 1:1.3.

[0028] In an embodiment of the present application, in step (2), the solvent is a mixed solvent of an organic solvent and water; the organic solvent can be an alcohol solvent; for example, ethanol.

[0029] In an embodiment of the present application, in step (2), the volume ratio of the organic solvent to water is 1: (0.8-1.2); for example, 1:1.

[0030] In an embodiment of the present application, the molar volume ratio of the compound III in step (1) to the solvent in step (2) is 1 mmol: (1.8-2.2) mL; preferably 1 mmol: 2 mL.

[0031] In an embodiment of the present application, in step (2), the reaction is carried out under reflux conditions; or the temperature of the reaction is 15-45°C; preferably 20-30°C.

[0032] In an embodiment of the present application, when the compound III is , or , in step (2), the temperature of the reaction is 15-45°C; preferably 20-30°C; when the compound III is In step (2), the reaction is carried out under reflux conditions.

[0033] In an embodiment of the present application, step (1) is terminated by the disappearance of compound III.

[0034] In an embodiment of the present application, the preparation method of compound IV further comprises the following post-treatment steps: concentration, dissolution, pH adjustment to ≤3, liquid separation, extraction, organic phase combination, washing and concentration; the concentration can be under reduced pressure; the dissolution can be methyl tert-butyl ether dissolution; the pH adjustment can be adjusted by hydrochloric acid, for example, concentrated hydrochloric acid; the extraction solvent can be methyl tert-butyl ether; the washing can be 10% sodium chloride solution.

[0035] In an embodiment of the present application, the raw materials for the preparation method of compound IV are the compound III, the base, the solvent in step (1) and the solvent in step (2).

[0036] In an embodiment of the present application, the preparation method of compound IV further comprises the preparation method of compound III, and the preparation method of compound III comprises the following step: in the presence of a base, compound II is subjected to a substitution reaction with 3-bromopropene in a solvent to obtain compound III.

[0037] ;

[0038] wherein, R 1 and R 2 are as defined in any embodiment of the present application.

[0039] In an embodiment of the present application, the compound II is , , or .

[0040] In an embodiment of the present application, the solvent is an organic solvent; preferably an ether solvent; the ether solvent can be tetrahydrofuran; for example, anhydrous tetrahydrofuran.

[0041] In an embodiment of the present application, the base is sodium hydride; for example, 60% sodium hydride.

[0042] In an embodiment of the present application, the mass-volume ratio of compound II to the solvent is 1 g: (2-8) mL; preferably 1 g: 5 mL.

[0043] In an embodiment of the present application, the molar ratio of compound II to the base is 1: (1-1.2); preferably 1:1.1.

[0044] In some embodiments of the present application, the molar ratio of compound II to 3-bromopropene is 1: (1-1.2); preferably 1:1.05.

[0045] In some embodiments of the present application, the base is added dropwise at a temperature of ≤5°C.

[0046] In some embodiments of the present application, the 3-bromopropene is added dropwise at a temperature of ≤5°C.

[0047] In some embodiments of the present application, the reaction step of the method for preparing compound III is as follows: after the addition of the base, the reaction is carried out at 0°C for 0.5-2 hours, for example, 1 hour; after the addition of 3-bromopropene, the reaction is carried out at 0-5°C for 0.5-2 hours, for example, 1 hour; the temperature is raised to 20-35°C, for example, 25°C; and the reaction is carried out until compound II is completely consumed, as monitored by TLC.

[0048] In some embodiments of the present application, the raw materials for the method for preparing compound III are the compound II, the solvent, the base and the 3-bromopropene.

[0049] The present application provides a method for preparing compound III, which is as described in any of the embodiments of the present application.

[0050] In some embodiments of the present application, the method for preparing compound III further comprises the following post-treatment steps: quenching, liquid separation, extraction and concentration; the quenching can be slow dropwise addition of the reaction solution into 5-6 mol / L dilute hydrochloric acid at a temperature of not higher than 10°C; the solvent for the liquid separation can be toluene; the extraction can be washing with water first and then with 5% sodium bicarbonate solution; and the concentration can be pressure concentration.

[0051] The present application provides a method for preparing compound I, which comprises the following steps,

[0052] Step 1, step (1): compound III is reacted in a solvent in the presence of a base under reflux conditions;

[0053] Step (2): the product obtained in step (1) is further reacted in a solvent to prepare compound IV;

[0054] ;

[0055] The method for preparing compound IV is as described in any of the embodiments of the present application.

[0056] Step 2: compound IV is reacted with triethylamine in a solvent to prepare compound V;

[0057] ;

[0058] Step 3, compound V is prepared by ring and reaction of compound IV in a solvent, in the presence of an acid and a catalyst;

[0059] .

[0060] In an embodiment of the present application, in step 2, the solvent is an organic solvent; preferably, an ether solvent and an alkane solvent; for example, methyl tert-butyl ether and n-heptane; more preferably, the volume ratio of the ether solvent and the alkane solvent is 1: (8-10); for example, 1:9.38.

[0061] In an embodiment of the present application, in step 2, the mass-volume ratio of compound IV to the solvent is 1 g: (8-12) mL; preferably, 1 g: 10.78 mL.

[0062] In an embodiment of the present application, in step 2, the mass ratio of compound IV to triethylamine is 1: (0.6-0.9); preferably, 1:0.79.

[0063] In an embodiment of the present application, in step 2, the triethylamine is first mixed with an alkane solvent, and then reacted with compound II.

[0064] In an embodiment of the present application, in step 2, the reaction temperature is room temperature; for example, 25°C.

[0065] In an embodiment of the present application, step 2 further comprises the following post-treatment steps: cooling, filtering and concentrating; the cooling can be to 0-5°C; the concentration can be under reduced pressure.

[0066] In an embodiment of the present application, in step 3, the solvent is an organic solvent; preferably, an aprotic solvent; for example, one or more selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone; for example, N,N-dimethylacetamide.

[0067] In an embodiment of the present application, in step 3, the catalyst is a base catalyst; the base catalyst can be a tertiary amine; for example, one or more selected from the group consisting of triethylamine, tripropylamine, tributylamine and N-methylmorpholine; for example, triethylamine.

[0068] In an embodiment of the present application, in step 3, the acid is an acid anhydride; for example, one or more selected from the group consisting of acetic anhydride, propionic anhydride and butyric anhydride; for example, acetic anhydride.

[0069] In an embodiment of the present application, in step 3, the mass-volume ratio of compound V to the solvent is 1 g: (1.3-1.8) mL; preferably, 1 g: 1.53 mL.

[0070] In one embodiment of the present application, in step 3, the molar ratio of compound V to the catalyst is 1:(0.06-0.1); preferably 1:0.089.

[0071] In one embodiment of the present application, in step 3, the molar ratio of compound V to the acid is 1:(1.2-1.8); preferably 1:1.69.

[0072] In one embodiment of the present application, in step 3, the temperature of the reaction is 100-125°C; preferably 115-117°C.

[0073] In one embodiment of the present application, in step 3, the time of the reaction is 4-6 h; preferably 5 h.

[0074] In one embodiment of the present application, step 3 further comprises the following post-treatment steps: cooling, adding solvent; extraction, combining organic phase; washing, concentrating and distilling; the cooling can be to 20-30°C; the added solvent can be water and n-hexane; the extraction solvent can be n-hexane; the washing can be with 5% sodium bicarbonate solution and water; the concentrating can be pressurized concentration; the distilling can be reduced pressure distillation; for example, 60-70°C, about 10 mmHg.

[0075] In one embodiment of the present application, the preparation method of compound I further comprises the preparation method of compound III, which is as described in any embodiment of the present application.

[0076] In one embodiment of the present application, the preparation method of compound I further comprises the preparation method of compound II, which is as follows: reacting n-butyraldehyde and compound A in a solvent under the condition of a catalyst to prepare compound II; wherein, compound II is as described in any embodiment of the present application.

[0077] ;

[0078] The compound A is malonic acid ester or .

[0079] In one embodiment of the present application, in the preparation method of compound II, the malonic acid ester is dimethyl malonate, diethyl malonate or di-tert-butyl malonate.

[0080] In one embodiment of the present application, in the preparation method of compound II, the catalyst is an acid catalyst and a base catalyst; the acid catalyst is preferably glacial acetic acid; the base catalyst is preferably azanomethylmorpholine or 4-methylpiperidine; for example, azanomethylmorpholine.

[0081] In some embodiments of the preparation method of compound II, the solvent is an organic solvent; preferably an alcohol solvent; more preferably methanol or ethanol.

[0082] In some embodiments of the preparation method of compound II, when compound A is dimethyl malonate, the solvent is methanol; when compound A is diethyl malonate, di-tert-butyl malonate or , the solvent is ethanol.

[0083] In some embodiments of the preparation method of compound II, the molar ratio of n-butyraldehyde to the catalyst is 1: (0.2-0.4); for example, 1:0.3.

[0084] In some embodiments of the preparation method of compound II, the molar ratio of n-butyraldehyde to compound A is 1: (1-1.2); for example, 1:1.1.

[0085] In some embodiments of the preparation method of compound II, the mass-volume ratio of n-butyraldehyde to the solvent is 1: (3-6); for example, 1:5.

[0086] In some embodiments of the preparation method of compound II, the method further comprises the following post-treatment steps: concentration, dissolution, hydrochloric acid (for example, 0.5M dilute hydrochloric acid), liquid separation, washing of the organic phase and concentration; the concentration can be reduced pressure concentration; the dissolution can be methyl tert-butyl ether dissolution; the washing can be sequential washing with 5% sodium bicarbonate and water.

[0087] The present application also provides a compound as shown in formula III,

[0088] ;

[0089] wherein the definition of the compound as shown in formula III is as described in any of the embodiments of the present application.

[0090] Without departing from the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining each preferred example of the present application.

[0091] The reagents and raw materials used in the present application are commercially available.

[0092] The positive progress effect of the present application is that the present application provides a preparation method of a key intermediate of melagabalin benzenesulfonate. The preparation method of the present application is simple, low in cost, high in yield and high in purity, and has a good application prospect in industrial production. DETAILED DESCRIPTION

[0093] The application will be further described in the following examples without limiting the application to the examples described. The experimental procedures in the following examples, unless otherwise indicated, were carried out according to conventional methods and conditions, or according to the manufacturer's instructions.

[0094] Example 1, Preparation of Compound II:

[0095]

[0096] To a reaction flask was added 7.2 g of n-butyraldehyde (100 mmol), malonic acid ester (110 mol), 1.51 g of azomethylmorpholine (15 mmol), 0.90 g of glacial acetic acid (15 mmol) under nitrogen protection, 36 mL of anhydrous alcohol was added to the reaction flask, and the reaction was heated to reflux until TLC showed that the n-butyraldehyde disappeared. Concentrated to dryness under reduced pressure, 36 mL of methyl tert-butyl ether, 20 mL of 0.5M dilute hydrochloric acid was added, stirred uniformly and separated, the organic phase was washed with 20 mL of 5% sodium bicarbonate, 20 mL of water, and concentrated to dryness under pressure to obtain compound II.

[0097] R 1 and R 2 methyl: malonic acid ester is dimethyl malonate, anhydrous alcohol is methanol, to obtain an oily liquid 18.0 g, yield 96.8%, 1H NMR (400 MHz, CDCl3): δ ppm 7.01 (t, 1H), 4.36 (s, 3H), 4.31 (s, 3H), 2.16-2.23 (m, 2H), 1.83-1.87 (m, 2H), 0.94 (t, 3H)

[0098] R 1 and R 2 ethyl: malonic acid ester is diethyl malonate, anhydrous alcohol is ethanol, to obtain an oily liquid 21.5 g, yield 100.0%, 1H NMR (400 MHz, CDCl3): δ ppm 7.03 (t, 1H), 4.31 (q, 2H), 4.26 (q, 2H), 2.17-2.24 (m, 2H), 1.84-1.87 (m, 2H), 1.33 (t, 3H), 1.31 (t, 3H), 0.95 (t, 3H)

[0099] R 1 and R 2For tert-butyl: malonic acid ester is di-tert-butyl malonate, and the anhydrous alcohol is ethanol, to give 26.8 g, yield 99.3%, 1H NMR (400 MHz, CDCl3): δ ppm 7.00 (t, 1H), 2.15-2.20 (m, 2H), 1.80-1.85 (m, 2H), 1.41 (s, 9H), 1.39 (s, 9H), 0.93 (t, 3H)

[0100] R 1 and R 2 are connected to form: : the anhydrous alcohol is ethanol, and the malonic acid ester is replaced by , to give a yellowish solid 19.5 g, yield 98.5%, 1H NMR (400 MHz, CDCl3): δ ppm 7.02 (t, 1H), 2.17-2.22 (m, 2H), 1.80-1.85 (m, 2H), 1.76 (s, 9H), 1.39 (s, 9H), 0.95 (t, 3H)

[0101] Example 2, preparation of compound III:

[0102]

[0103] To the reaction bottle, 100 mmol of compound II, anhydrous tetrahydrofuran (1 g of compound II / 5 mL of tetrahydrofuran), cooling to 0°C, temperature control not higher than 5°C, slowly add 2.64 g of NaH (110 mmol, 60%), then temperature control 0°C, stirring for 1 hour, temperature control not higher than 5°C, slowly drop 12.7 g of 3-bromopropene (105 mmol), after adding, stirring for 1 hour, warming to 25°C, incubation until TLC shows that compound II disappears. Temperature control not higher than 10°C, slowly drop the reaction liquid into 30 mL of 5-6 mol / L dilute hydrochloric acid, after adding, add 100 mL of toluene, separate the liquid. The organic phase is washed with 30 mL of water, 30 mL of 5% sodium bicarbonate solution, concentrated to dryness under pressure to give compound III.

[0104] R 1 and R 2methyl: oily liquid, 20.8 g, yield 92.3%, 1H NMR (400 MHz, CDC13): δ ppm 7.65 (d, 1H), 5.64-5.75 (m, 1H), 4.96-5.05 (m, 2H), 4.30 (s, 3H), 4.21 (s, 3H), 3.70-3.78 (m, 1H), 2.34-2.42 (m, 1H), 2.16-2.25 (m, 1H), 1.45-1.58 (m, 2H), 0.93 (t, 3H)

[0105] R 1 and R 2 ethyl: oily liquid, 23.6 g, yield 92.9%, 1H NMR (400 MHz, CDC13): δ ppm 7.63 (d, 1H), 5.66-5.77 (m, 1H), 4.97-5.06 (m, 2H), 4.26 (s, 2H), 4.19 (s, 2H), 3.69-3.78 (m, 1H), 2.33-2.42 (m, 1H), 2.12-2.21 (m, 1H), 1.46-1.58 (m, 2H), 1.35 (t, 3H), 1.32 (t, 3H), 0.92 (t, 3H)

[0106] R 1 and R 2 tert-butyl: oily liquid, 30.5 g, yield 98.4%, 1H NMR (400 MHz, CDC13): δ ppm 7.64 (d, 1H), 5.65-5.77 (m, 1H), 4.97-5.08 (m, 2H), 3.68-3.78 (m, 1H), 2.33-2.42 (m, 1H), 2.12-2.21 (m, 1H), 1.62-1.72 (m, 1H), 1.42-1.53 (m, 1H), 1.41 (s, 9H), 1.39 (s, 9H), 0.93 (t, 3H)

[0107] R 1 and R 2 are connected to form: : yellow solid, 23.0 g, yield 98.7%, 1H NMR (400 MHz, CDC13): δ ppm 7.63 (d, 1H), 5.66-5.77 (m, 1H), 4.97-5.06 (m, 2H), 3.69-3.78 (m, 1H), 2.33-2.42 (m, 1H), 2.12-2.21 (m, 1H), 1.74 (s, 6H), 1.62-1.72 (m, 1H), 1.42-1.53 (m, 1H), 0.92 (t, 3H)

[0108] Example Three, Preparation of Compound IV:

[0109]

[0110] To the reaction vessel was added 100 mmol of compound III, 100 mL of ethanol, 7.28 g of sodium hydroxide (130 mmol), and the reaction was heated to reflux. The reaction was maintained at reflux until compound III was consumed by TLC. The reaction was cooled to 20-30 °C, and 100 mL of water was added. The reaction was maintained at 20-30 °C until the intermediate was consumed by TLC. The reaction was concentrated under reduced pressure to about 100 mL. 100 mL of methyl tert-butyl ether was added, and the pH was adjusted to < 3 with concentrated hydrochloric acid. The aqueous phase was extracted with 50 mL of methyl tert-butyl ether. The organic phases were combined and washed with 10% sodium chloride solution (50 mL x 2). The organic phase was concentrated under reduced pressure to an oil. MS (M-H + ): 153.

[0111] R 1 and R 2 are methyl, 15.0 g, yield 97.7%.

[0112] R 1 and R 2 are ethyl, 14.8 g, yield 96.1%.

[0113] R 1 and R 2 are connected to form: , 14.9 g, yield 96.7%.

[0114] Example Four, Preparation of Compound IV:

[0115]

[0116] To the reaction vessel was added 31.0 g of compound III-tBu (100 mmol), 100 mL of ethanol, 7.28 g of sodium hydroxide (130 mmol), and the reaction was heated to reflux. After the reaction was complete, 100 mL of water was added and the reaction was allowed to continue until the reaction was complete. The reaction was concentrated under reduced pressure to about 100 mL. 100 mL of methyl tert-butyl ether was added, and the pH was adjusted to < 3 with concentrated hydrochloric acid. The aqueous phase was extracted with 50 mL of methyl tert-butyl ether. The organic phases were combined and washed with 10% sodium chloride solution (50 mL x 2). The organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to 30-40 mL. A solution of 12.1 g of triethylamine in 150 mL of n-heptane was added dropwise, and the reaction was cooled to 0-5 °C. The reaction was filtered and dried under reduced pressure to give a white solid 24.0 g, with a yield of 94.1%.

[0117] Example Five, Preparation of Compound V:

[0118]

[0119] To the reaction vessel was added 31.0 g of compound III-tBu (100 mmol), 100 mL of ethanol, 7.28 g of sodium hydroxide (130 mmol), and the reaction was heated to reflux. After the reaction was complete, 100 mL of water was added and the reaction was allowed to continue until the reaction was complete. The reaction was concentrated under reduced pressure to about 100 mL. 100 mL of methyl tert-butyl ether was added, and the pH was adjusted to < 3 with concentrated hydrochloric acid. The aqueous phase was extracted with 50 mL of methyl tert-butyl ether. The organic phases were combined and washed with 10% sodium chloride solution (50 mL x 2). The organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to 30-40 mL. A solution of 12.1 g of triethylamine in 150 mL of n-heptane was added dropwise, and the reaction was cooled to 0-5 °C. The reaction was filtered and dried under reduced pressure to give a white solid 24.0 g, with a yield of 94.1%.

[0120] Example Six, Preparation of Compound V:

[0121]

[0122] To the reaction vessel was added 31.0 g of compound III-tBu (100 mmol), 100 mL of ethanol, 7.28 g of sodium hydroxide (130 mmol), and the reaction was heated to reflux. After the reaction was complete, 100 mL of water was added and the reaction was allowed to continue until the reaction was complete. The reaction was concentrated under reduced pressure to about 100 mL. 100 mL of methyl tert-butyl ether was added, and the pH was adjusted to < 3 with concentrated hydrochloric acid. The aqueous phase was extracted with 50 mL of methyl tert-butyl ether. The organic phases were combined and washed with 10% sodium chloride solution (50 mL x 2). The organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to 30-40 mL. A solution of 12.1 g of triethylamine in 150 mL of n-heptane was added dropwise, and the reaction was cooled to 0-5 °C. The reaction was filtered and dried under reduced pressure to give a white solid 24.0 g, with a yield of 94.1%.

[0123] R 1 and R2 was methyl, 23.5 g was obtained, yield 92.2%.

[0124] R 1 and R 2 was ethyl, 23.7 g was obtained, yield 92.9%.

[0125] R 1 and R 2 were connected to form: , 21.6 g was obtained, yield 84.7%.

[0126] Example Seven, Preparation of Compound V:

[0127]

[0128] To the reaction bottle, 27.0 g of compound II-tBu (100 mmol), 135 mL of anhydrous tetrahydrofuran were added, and the temperature was lowered to 0°C, and 2.64 g of NaH (110 mmol, 60%) was slowly added while controlling the temperature not to exceed 5°C, and then the temperature was controlled at 0°C for 1 hour, and 12.7 g of 3-bromopropene (105 mmol) was slowly added dropwise while controlling the temperature not to exceed 5°C, and after the addition was completed, it was stirred for 1 hour, and the temperature was raised to 25°C, and the reaction was carried out until TLC showed that compound II disappeared. To the reaction bottle, 70 mL of ethanol and 7.28 g of sodium hydroxide (130 mmol) were added, and the temperature was raised while distilling, and when the internal temperature rose to about 80°C, the reaction was carried out until TLC showed that compound III-tBu disappeared. Then 100 mL of water was added, and the reaction was continued to reflux until the reaction was completed, and it was concentrated under reduced pressure to about 100 mL. 100 mL of methyl tert-butyl ether was added, and the pH was adjusted to ≤3 with concentrated hydrochloric acid, and the aqueous phase was separated, and 50 mL of methyl tert-butyl ether was added to extract the aqueous phase. The organic phase was washed with 10% sodium chloride solution (50 mL*2), and the organic phase was dried over anhydrous sodium sulfate. It was concentrated under reduced pressure to 30-40 mL, and 12.1 g of triethylamine dissolved in 150 mL of n-heptane was added dropwise, and after the addition was completed, the temperature was lowered to 0-5°C, and it was filtered and dried under reduced pressure to obtain a white solid 15.6 g, yield 61.2%.

[0129] Example Eight, Preparation of Compound I:

[0130]

[0131] To a reaction flask was added 255 g of compound V (1 mol), 390 mL of N,N-dimethylacetamide, 159 mL of acetic anhydride, 89.9 g of triethylamine (89.0 mmol). The reaction was heated to 115-117°C with stirring and maintained for 5 hours. The reaction was cooled to room temperature, and 1090 mL of water, 780 mL of n-hexane was added at a temperature not higher than 30°C, and then separated after stirring. The aqueous phase was extracted with n-hexane (390 mL*2). The organic phase was combined and washed once with 5% sodium bicarbonate solution (160 mL) and water (160 mL). The organic phase was concentrated under pressure, and then distilled under reduced pressure (60-70°C, about 10 mmHg) to obtain compound I 103 g as a colorless liquid, yield: 75.7%. Purity 99.82%.1H NMR (400 MHz, CDCl3): δ ppm 5.22(t, 1H), 2.18-4.19(m, 1H), 3.16-3.21(m, 1H), 2.80-2.81(m, 2H), 2.28-2.32(m, 1H), 2.12(q, 2H), 1.06(s, 3H).

Claims

1. A method for preparing compound IV, characterized in that, It includes the following steps: Step (1): Compound III reacts under reflux conditions in a solvent in the presence of a base; the solvent is an organic solvent; Step (2): In a solvent, the product obtained in step (1) continues to react to prepare compound IV; the solvent is a mixture of organic solvent and water; ； Among them, R 1 and R 2 Independently a C1-C6 alkyl group; or R 1 and R 2 Connected to form .

2. The method for preparing compound IV according to claim 1, characterized in that, R 1 and R 2 same.

3. The method for preparing compound IV according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The alkyl group of C1-C6 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; (2) In step (1), the base is an inorganic base; (3) In step (1), the molar volume ratio of compound III to the solvent is 1 mmol: (0.8-1.2) mL; (4) In step (1), the molar ratio of compound III to the base is 1:(1-2). (5) The molar volume ratio of compound III in step (1) to the solvent in step (2) is 1 mmol: (1.8-2.2) mL; (6) In step (2), the reaction is carried out under reflux conditions; or the temperature of the reaction is 15-45℃; (7) Step (1) ends with the disappearance of compound III; and (8) The raw materials for the preparation method of compound IV are compound III, the base, the solvent in step (1) and the solvent in step (2).

4. The method for preparing compound IV according to claim 3, characterized in that, The alkyl groups of C1-C6 are independently methyl, ethyl, or tert-butyl.

5. The method for preparing compound IV according to claim 4, characterized in that, It satisfies one or more of the following conditions: (1) Compound III is , , or ; (2) In step (1), the solvent is an alcohol solvent; (3) In step (1), the alkali is an alkali metal hydroxide; (4) In step (1), the molar volume ratio of compound III to the solvent is 1 mmol: 1 mL; (5) In step (1), the molar ratio of compound III to the base is 1:1.3; (6) In step (2), the organic solvent is an alcohol solvent; (7) In step (2), the volume ratio of the organic solvent to water is 1:(0.8-1.2); (8) The molar volume ratio of compound III in step (1) to the solvent in step (2) is 1 mmol: 2 mL; (9) In step (2), the reaction temperature is 20-30℃; and (10) When compound III is , or In step (2), the reaction temperature is 15-45℃; when compound III is In step (2), the reaction is carried out under reflux conditions.

6. The method for preparing compound IV according to claim 5, characterized in that, It satisfies one or more of the following conditions: (1) Compound III is , or ; (2) In step (1), the solvent is ethanol; (3) In step (1), the alkali is potassium hydroxide and / or sodium hydroxide; (4) In step (2), the organic solvent is ethanol; (5) In step (2), the volume ratio of the organic solvent to water is 1:1; and (6) When compound III is , or In step (2), the reaction temperature is 20-30℃.

7. The method for preparing compound IV according to claim 1, characterized in that, The preparation method of compound IV also includes a preparation method of compound III, wherein the preparation method of compound III includes the following steps: in a solvent and in the presence of a base, compound II undergoes a substitution reaction with 3-bromopropene to prepare compound III; ； Among them, R 1 and R 2 The definition is as described in any one of claims 1-6.

8. The method for preparing compound IV according to claim 7, characterized in that, It satisfies one or more of the following conditions; (1) The compound II is , , or ; (2) The solvent is an organic solvent; (3) The alkali is sodium hydride; (4) The mass-to-volume ratio of compound II to the solvent is 1 g:(2-8) mL; (5) The molar ratio of compound II to the base is 1:(1-1.2); (6) The molar ratio of compound II to 3-bromopropene is 1:(1-1.2); (7) The alkali is added dropwise at ≤5℃; (8) The 3-bromopropene is added dropwise at ≤5℃; (9) The reaction steps of the preparation method of compound III are as follows: after adding alkali, react at 0°C for 0.5-2 hours; add 3-bromopropene, react at 0-5°C for 0.5-2 hours; raise the temperature to 20-35°C; react until compound II is completely reacted as monitored by TLC; and (10) The raw materials for the preparation method of compound III are compound II, solvent, alkali and 3-bromopropylene.

9. The method for preparing compound IV according to claim 8, characterized in that, It satisfies one or more of the following conditions; (1) The solvent is an ether solvent; (2) The alkali is 60% sodium hydride; (3) The mass-to-volume ratio of compound II to the solvent is 1 g: 5 mL; (4) The molar ratio of compound II to the base is 1:1.1; (5) The molar ratio of compound II to 3-bromopropene is 1:1.05; and (6) The reaction steps of the preparation method of compound III are as follows: after adding alkali, react at 0°C for 1 hour; add 3-bromopropene and react at 0-5°C for 1 hour; heat to 25°C; and react until compound II is completely reacted as monitored by TLC.

10. The method for preparing compound IV according to claim 9, characterized in that, The ether solvent is tetrahydrofuran.

11. The method for preparing compound IV according to claim 10, characterized in that, The ether solvent is anhydrous tetrahydrofuran.

12. A method for preparing compound I, characterized in that, It includes the following steps, Step 1, Step (1): In a solvent, in the presence of a base, compound III reacts under reflux conditions; Step (2): In a solvent, the product obtained in step (1) continues to react to prepare compound IV; ； The method for preparing compound IV is as described in any one of claims 1-11; Step 2: Compound IV is reacted with triethylamine in a solvent to prepare compound V; ； Step 3: In a solvent, in the presence of acid and catalyst, compound V undergoes a cyclization reaction to prepare compound I; 。 13. The method for preparing compound I according to claim 12, characterized in that, It satisfies one or more of the following conditions; (1) In step 2, the solvent is an organic solvent; (2) In step 2, the mass-to-volume ratio of compound IV to the solvent is 1 g: (8-12) mL; (3) In step 2, the mass ratio of compound IV to triethylamine is 1:(0.6-0.9). (4) In step 2, the triethylamine is first mixed with an alkane solvent; then reacted with compound II; (5) In step 2, the reaction temperature is room temperature; (6) In step 3, the solvent is an organic solvent; (7) In step 3, the catalyst is an alkaline catalyst; (8) In step 3, the acid is an acid anhydride; (9) In step 3, the mass-to-volume ratio of compound V to solvent is 1 g: (1.3-1.8) mL; (10) In step 3, the molar ratio of compound V to the catalyst is 1:(0.06-0.1). (11) In step 3, the molar ratio of compound V to acid is 1:(1.2-1.8). (12) In step 3, the reaction temperature is 100-125℃; (13) In step 3, the reaction time is 4-6 h; and (14) The method for preparing compound I further includes a method for preparing compound III, wherein the method for preparing compound III is as described in any one of claims 7-11.

14. The method for preparing compound I according to claim 13, characterized in that, It satisfies one or more of the following conditions; (1) In step 2, the solvent is an ether solvent or an alkane solvent; (2) In step 2, the mass-to-volume ratio of compound IV to the solvent is 1 g: 10.78 mL; (3) In step 2, the mass ratio of compound IV to triethylamine is 1:0.79; (4) In step 2, the reaction temperature is 25°C; (5) In step 3, the solvent is an aprotic solvent; (6) In step 3, the alkaline catalyst is a tertiary amine; (7) In step 3, the acid is selected from one or more of acetic anhydride, propionic anhydride and butyric anhydride; (8) In step 3, the mass-to-volume ratio of compound V to solvent is 1 g: 1.53 mL; (9) In step 3, the molar ratio of compound V to the catalyst is 1:0.089; (10) In step 3, the molar ratio of compound V to acid is 1:1.69; (11) In step 3, the reaction temperature is 115-117℃; and (12) In step 3, the reaction time is 5 h.

15. The method for preparing compound I according to claim 14, characterized in that, It satisfies one or more of the following conditions; (1) In step 2, the solvent is methyl tert-butyl ether and n-heptane; (2) In step 3, the solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolium ketone; (3) In step 3, the base catalyst is selected from one or more of triethylamine, tripropylamine, tributylamine, and N-methylmorpholine; and (4) In step 3, the acid is acetic anhydride.

16. The method for preparing compound I according to claim 15, characterized in that, It satisfies one or more of the following conditions; (1) In step 2, the volume ratio of the ether solvent to the alkane solvent is 1:(8-10). (2) In step 3, the solvent is N,N-dimethylacetamide; and (3) In step 3, the alkaline catalyst is triethylamine.

17. The method for preparing compound I according to claim 16, characterized in that, In step 2, the volume ratio of the ether solvent to the alkane solvent is 1:9.

38.

18. The method for preparing compound I according to claim 17, characterized in that, The method for preparing compound I further includes a method for preparing compound II, wherein compound II is prepared by reacting n-butyraldehyde with compound A in a solvent under catalytic conditions. ； Wherein, compound II is defined as described in claim 7 or 8; The compound A is a malonate or .

19. The method for preparing compound I according to claim 18, characterized in that, The preparation method of compound II satisfies one or more of the following conditions; (1) In the preparation method of compound II, the malonic acid ester is dimethyl malonate, diethyl malonate or ditert-butyl malonate; (2) In the preparation method of compound II, the catalyst is an acid catalyst and a base catalyst; (3) In the preparation method of compound II, the solvent is an organic solvent; (4) In the preparation method of compound II, the molar ratio of n-butyraldehyde to the catalyst is 1:(0.2-0.4). (5) In the preparation method of compound II, the molar ratio of n-butyraldehyde to compound A is 1:(1-1.2); and (6) In the preparation method of compound II, the mass-volume ratio of n-butyraldehyde to the solvent is 1:(3-6).

20. The method for preparing compound I according to claim 19, characterized in that, The preparation method of compound II satisfies one or more of the following conditions; (1) In the preparation method of compound II, the acid catalyst is glacial acetic acid; (2) In the preparation method of compound II, the base catalyst is N-methylmorpholine or 4-methylpiperidine; (3) In the preparation method of compound II, the solvent is an alcohol solvent; (4) In the preparation method of compound II, the molar ratio of n-butyraldehyde to the catalyst is 1:0.3; (5) In the preparation method of compound II, the molar ratio of n-butyraldehyde to compound A is 1:1.1; and (6) In the preparation method of compound II, the mass-volume ratio of n-butyraldehyde to the solvent is 1:

5.

21. The method for preparing compound I according to claim 20, characterized in that, The preparation method of compound II satisfies one or two of the following conditions; (1) In the preparation method of compound II, the base catalyst is N-methylmorpholine; and (2) In the preparation method of compound II, the solvent is methanol or ethanol.

22. The method for preparing compound I according to claim 21, characterized in that, In the preparation method of compound II, when compound A is dimethyl malonate, the solvent is methanol; when compound A is diethyl malonate, di-tert-butyl malonate, or... In this case, the solvent is ethanol.

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